Inhibition of male fertility with aliphatic sulfamates

ABSTRACT

Aliphatic sulfamates are prepared by reacting an alkanediol with sulfamoyl chloride. The aliphatic sulfamates are novel compounds and are useful in the control of fertility in male animals.

This is a division of application Ser. No. 537,613, filed Dec. 30, 1974now U.S. Pat. No. 3,997,585.

BACKGROUND OF THE INVENTION

The present invention relates to novel aliphatic sulfamates. Thesulfamates may be represented by the formula: ##STR1## wherein n is aninteger from 0-8 and X and Y are hydrogen, provided that when n is 1, Xand Y are hydrogen, lower alkyl having 1-3 carbon atoms, aryl such asphenyl or arylalkyl such as benzyl, phenethyl and the like, and R₁ andR₂ are hydrogen, alkyl having 1-7 carbon atoms, aryl, arylalkyl such asbenzyl, phenethyl, phenylpropyl and the like, cycloalkyl such ascyclopentyl, cyclohexyl and the like, or R₁ and R₂ together with thenitrogen atom to which they are attached form a saturated heterocyclicring. Preferred among these compounds are those compounds wherein R₁ andR₂ are hydrogen.

The novel aliphatic sulfamates of the present invention are prepared byreacting an alkanediol with a sulfamoyl halide in a suitable solvent inthe presence of a strong base. Suitable alkanediols which may beemployed include 1,2-ethanediol, 1,3-propanediol, 1,4-butanediol,1,5-pentanediol, 1,10-decanediol and the like. As the halide reactant,sulfamoyl chloride and N,N-di or mono substituted sulfamoyl halides maybe employed. Bases such as sodium hydride, sodium amide, sodiumhydroxide, pyridine and tributyltin are examples of suitable strongbases. Examples of solvents which may be employed include1,2-dimethoxyethane, ether, tetrahydrofuran, diglyme and p-dioxane. Thereaction with the sulfamoyl halide may be carried out at roomtemperature, but it is preferred to carry out the reaction at atemperature between 0°-10° C. The sulfamate is obtained from thereaction mixture by techniques known to those skilled in the art.

The novel aliphatic sulfamates are useful in the control of fertility inmale animals. The compounds are capable of interfering with sperm asthey sojourn in the epididymis and thus result in what is known asfunctional sterility, i.e. the gametes remain morphologically normal andshow motility but normal fertilization is not achieved. Generally dosagelevels of from about 5-200 mg./kg. are effective in inducing functionalsterility. The preferred dosage range is from about 10-150 mg./kg. Inaddition to causing functional sterility of epididymal sperm, the novelsulfamates have antiandrogenic properties as manifested by inhibition ofthe size of the ventral prostate.

The general procedure followed to determine the activity of compoundswhich inhibit male fertility by altering the functional capacity ofepididymal sperm is as follows:

A two week dosing period (i.e., the approximate period required forsperm transport through the epididymis) enables separation of thosedrugs which affect epididymal sperm maturation and/or function from theantispermatogenic agents which have a longer delay in the onset ofsterility. Each individual test involves 5 male rats (250-300 g.) cagedtogehter in air conditioned animal quarters and maintained on laboratorychow and tap water ad libitum. The compound to be tested is dissolved orsuspended in appropriate vehicles (usually methylcellulose) andadministered daily (usually i.g.) for 14 consecutive days. Controlanimals receive the vehicle only. At the end of the 14th day oftreatment each male is individually caged with a proestrus female.Vaginal smears are checked the following morning for evidence ofpositive mating, and those males failing to mate are recohabited withproestrus females the following night. Males are sacrificed andautopsied the day after cohabitation for a gross examination of testes,epididymides, and accessory sex organs. Tissue samples of these organsare preserved for histological processing if observation yields apossible effect. Females (regardless of sperm presence in the vaginalwashings) are autopsied 14 days after cohabitation to examine forpregnancy.

The inability of females to produce a viable embryo following asuccessful mating with treated males (two weeks of medication) is usedas a measure of functional infertility. The number of males mating ofthose cohabited gives a gross indication of the drug's effect on libido.The size of the accessory sex organs provides an indication of theeffect on androgen production. Microscopic analysis of epididymal spermprovides information on sperm quality (motility and morphology) andquantity.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating and not limiting theinvention.

EXAMPLE 1 1,2-Bis-O-sulfamyl-1,2-ethanediol

A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added toa solution of ethylene glycol (3.1 g.; 0.05 mol.) in 1,2-dimethoxyethane(100 ml.). The resulting suspension is stirred at room temperature for 2hours and then cooled to +4° C. Sulfamoyl chloride (20.79 g.; 0.18 mol.)is dissolved in 1,2-dimethoxyethane (400 ml.) and added dropwise to thesolution with stirring. The reaction mixture is stirred at +4° C for anadditional 24 hours. A precipitate forms which is filtered off and thefiltrate is concentrated. The residue is partitioned between heptane andmethanol, and the methanol solution is concentrated to a syrup whichcrystallizes from ethyl acetate to yield 6.1 g. (58%) of1,2-bis-O-sulfamyl-1,2-ethanediol, m.p. 96.5°-99° C. When in the aboveprocedure 1,5-pentanediol is employed in place of ethylene glycol,1,5-bis-O-sulfamyl-1,5-pentanediol is obtained.

EXAMPLE 2 1,10-Bis-O-sulfamyl-1,10 -decanediol

A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added toa solution of 1,10-decanediol (8.71 g.; 0.05 mol.) in1,2-dimethoxyethane (100 ml.). The resulting solution is stirred at roomtemperature for 2 hours and then cooled to +4° C. Sulfamoyl chloride(20.79 g.; 0.18 mol.) is dissolved in 1,2-dimethoxyethane (400 ml.) andadded dropwise to the solution with stirring. The reaction mixture isstirred at +4° C for an additional 48 hours. A precipitate forms whichis filtered off and the filtrate is concentrated. The residue ispartitioned between heptane and methanol and the methanol solution isconcentrated to a syrup which crystallizes from ethyl acetate to yield6.0 g. (36%) of 1,10-bis-O-sulfamyl-1,10-decanediol, m.p. 129°-131° C.

When in the above procedure 1,6-hexanediol is employed in place of1,10-decanediol, 1,6-bis-O-sulfamyl-1,6-hexanediol is obtained.

EXAMPLE 3 1,4-Bis-O-sulfamyl-1,4-butanediol

A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added toa solution of 1,4-butanediol (4.5 g.; 0.05 mol.) in 1,2-dimethoxyethane(100 ml.). The resulting solution is stirred at room temperature for 2hours and then cooled to +4° C. Sulfamoyl chloride (20.79 g.; 0.18 mol.)is dissolved in 1,2-dimethoxyethane (400 ml.) and added dropwise to thesolution with stirring. The reaction mixture is stirred at +4° C for anadditional 48 hours. A precipitate forms which is filtered off and thefiltrate is concentrated. The residue is partitioned between heptane andmethanol and the methanol solution is concentrated to a syrup whichcrystallizes from ethyl alcohol to yield 5.5 g. (47%) of1,4-bis-O-sulfamyl-1,4-butanediol, m.p. 126°-129° C.

When in the above procedure 1,7-heptanediol is employed in place of1,4-butanediol, 1,7-bis-O-sulfamyl-1,7-heptanediol is obtained.

EXAMPLE 4 1,3-Bis-O-sulfamyl-1,3-propanediol

A 57% oil dispersion of sodium hydride (25.4 g.; 0.60 mol.) is added toa solution of 1,3-propanediol (11.41 g.; 0.15 mol.) in1,2-dimethoxyethane (100 ml.). The resulting solution is stirred at roomtemperature for 2 hours and then cooled to +4° C. Sulfamoyl chloride(62.37 g.; 0.54 mol.) is dissolved in 1,2-dimethoxyethane (400 ml.) andadded dropwise to the solution with stirring. The reaction mixture isstirred at +4° C for an additional 24 hours. A precipitate forms whichis filtered off and the filtrate is concentrated. The residue ispartitioned between heptane and methanol and the methanol solution isconcentrated to a syrup. The residue is washed with heptane andchromatographed through SilicAR, CC-7 using 50% acetone-chloroform asthe eluent. The fractions are collected and upon removal of the solvent1,3-bis-O-sulfamyl-1,3-propanediol is obtained as a crystalline residue,m.p. 85°-87.5° C.

When in the above procedure 1,8-octanediol and 1,9-nonanediol areemployed in place of 1,3-propanediol, 1,8-bis-O-sulfamyl-1,8-octanedioland 1,9-bis-O-sulfamyl 1,9-nonanediol respectively are obtained.

EXAMPLE 5 2-Methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol

To a solution of 10 g. (0.076 mol.) of 2-methyl-2-propyl-1,3-propanediolin 200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodiumhydride followed by an additional 400 ml. of dimethoxyethane. Afterstirring overnight the suspension is cooled to 4° C and a solution of31.2 g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethaneis added dropwise. The resulting suspension is stirred overnight at roomtemperature. The mixture is then filtered, the filtrate is concentratedand the residue washed with heptane. The residue is then chromatographedthrough SilicAR, CC-7 and eluted with 25% acetone-chloroform. The solidobtained after removel of the solvent is crystallized from a mixture ofethyl acetate-hexane-methylene chloride to afford2-methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol, m.p. 92°-94° C.

When in the above procedure 2-ethyl-2-propyl-1,3-propanediol,2,2-dimethyl-1,3-propanediol and 2-methyl-1,3-propanediol are employedinstead of 2-methyl-2-propyl-1,3-propanediol,2-ethyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol,2,2-dimethyl-1,3-bis-O-sulfamyl-1,3-propanediol and2-methyl-1,3-bis-O-sulfamyl-1,3-propanediol, respectively, are obtained.

EXAMPLE 6 2,2-Diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol

To a solution of 17.3 g. (0.076 mol.) of 2,2-diphenyl-1,3-propanediol in200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodiumhydride followed by an additional 400 ml. of dimethoxyethane. Afterstirring overnight the suspension is cooled to 4° C. A solution of 31.2g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethane isthen added dropwise. The suspension is stirred overnight at roomtemperature. After filtering the mixture the filtrate is concentratedand the residue washed with heptane. Chromatography on SilicAR, CC-7,followed by crystallization affords2,2-diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol.

When in the above procedure 2,2-dibenzyl-1,3-propanediol and2,2-dicyclohexyl-1,3-propanediol are employed in place of2,2-diphenyl-1,3-propanediol,2,2-dibenzyl-1,3-bis-O-sulfamyl-1,3-propanediol and2,2-dicyclohexyl-1,3-bis-O-sulfamyl-1,3-propanediol are obtained.

EXAMPLE 7 1,2-Bis-O-(N,N-dimethylsulfamyl)-1,2-ethanediol

A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added toa solution of ethylene glycol (3.1 g.; 0.05 mol.) in 1,2-dimethoxyethane(100 ml.). The resulting suspension is stirred at room temperature for 2hours and then cooled to +4° C. N,N-dimethylsulfamoyl chloride, 25.8 g.(0.18 mol.), is dissolved in 1,2-dimethoxyethane (400 ml.) and addeddropwise to the solution with stirring. The reaction mixture is stirredat +4° C for an additional 24 hours. A precipitate forms which isfiltered off and the filtrate is concentrated. The residue ispartitioned between heptane and methanol, and the methanol solution isconcentrated to a syrup which crystallizes from ethyl acetate to yield1,2-bis-O-(N,N-dimethylsulfamyl)-1,2-ethanediol.

When in the above procedure N,N-diphenylsulfamoyl chloride andN-ethylsulfamoyl chloride are employed in place of sulfamoyl chloride,1,2-bis-O-(N,N-diphenylsulfamyl)-1,2-ethanediol and1,2-bis-O-(N-ethylsulfamyl)-1,2-ethanediol are obtained.

When in the above procedure N-cyclohexylsulfamoyl chloride,N,N-dicyclopentylsulfamoyl chloride, N,N-dibenzylsulfamoyl chloride and1-piperidylsulfonyl chloride are employed in place of sulfamoylchloride, 1,2-bis-O-(N-cyclohexysulfamyl)-1,2-ethanediol,1,2-bis-O-(N,N-dicyclopentylsulfamyl)-1,2-ethanediol,1,2-bis-O-(N,N-dibenzylsulfamyl)-1,2-ethanediol and1,2-bis-(1-piperidylsulfonyl)-1,2-ethanediol are obtained.

What is claimed is:
 1. A method of inhibiting fertility in male animalscomprising administering to a male animal an effective amount of acompound of the formula ##STR2## wherein n is an integer from 0 to 8 andX and Y are hydrogen, provided that when n is 1, X and Y are hydrogen,lower alkyl having 1-3 carbon atoms, phenyl, benzyl or phenethyl, R₁ andR₂ are hydrogen, alkyl having 1-7 carbon atoms, phenyl, benzyl,phenethyl or cycloalkyl having 5-6 carbon atoms, and R₁ and R₂ togetherwith the nitrogen are piperidyl.
 2. The method of claim 1 wherein saidcompound is 1,2-bis-O-sulfamyl-1,2-ethanediol.
 3. The method of claim 1wherein said compound is 1,3-bis-O-sulfamyl-1,3-propanediol.
 4. Themethod of claim 1 wherein said compound is1,4-bis-O-sulfamyl-1,4-butanediol.
 5. The method of claim 1 wherein saidcompound is 1,10-bis-O-sulfamyl-1,10-decanediol.